Many mouse plasmacytomas produce homogeneous myeloma proteins that bind nitrophenyl or phosphorylcholine groups in a manner analogous to that of normal antibody. In spite of extensive chemical characterization the binding site of myeloma proteins or normal antibodies has not been identified. The goal of this research is to develop methods by which mutant plasmacytoma cells can be isolated. Since the plasmacytoma cells have immunoglobulin on their surface which is identical to that secreted, selection of mutant cell by their altered antigen-binding capacity selects also for altered myeloma proteins. The selection methods will involve several approaches including (1) physical separation of cells by differential adsorption to hapten-specific immunoadsorbents, (2) selective killing of cells on the basis of hapten-binding by using hapten-coupled toxins, such as diptheria toxins, or (3) selective protection of myeloma cells by hapten-coupled peroxidase from lethal exposure to peroxide. Screening of tumor populations for mutants will make use of a modification of the Jerne plaque technique which permits determination of affinity or cross-reactivity of individual antibody-secreting cells. After selection, cells will be cloned on soft agar. Myeloma proteins that differ only in the binding site will allow a precise characterization of this most versatile region of all proteins. BIBLIOGRAPHIC REFERENCES: Claflin, J.L., and Davie, J.M. 1975. Clonal natuue of the immune response to phosphorylcholine (PC) V. Cross-idiotypic specificity among heavy chains of murine anti-PC antibodies and PC-binding myeloma proteins. J. Exp. Med. 141 pp. 1073-1083. Claflin, J.L., Rudikoff, S., Potter, M. and Davie, J.M. 1975. Structural, functional, and idiotypic characteristics of a phosphorylcholine-binding IgA myeloma protein of C57BL/ka allotype. J. Exp. Med. 141 pp. 608-619.